Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

Abstract

Skin keratinocytes express tissue factor (TF) and are highly associated with skin wound healing. Although it has been demonstrated that perivascular TF expression in granulation tissue formed after dermal injury is downregulated during healing, studies of the mechanism of factor (F) VII, a TF ligand, in skin wound healing are lacking. We reported the use of a dermal punch model to demonstrate that low-expressing FVII mice (~1% of wild type [WT]) exhibited impaired skin wound healing compared with WT controls. These low-FVII mice showed defective reepithelialization and reduced inflammatory cell infiltration at wound sites. This attenuated reepithelialization was associated with diminished expression of the transcription factor early growth response 1 (Egr-1). In vitro, Egr-1 was shown to be essential for the FVIIa-induced regulation of keratinocyte migration and inflammation. Both Egr-1 upregulation and downstream inflammatory cytokine appearance in keratinocytes depended on FVIIa/TF/protease-activated receptor 2 (PAR-2)-induced signaling and did not require subsequent generation of FXa and thrombin. The participation of Egr-1 in FVIIa-mediated regulation of keratinocyte function was confirmed by use of Egr-1-deficient mice, wherein a significant delay in skin wound healing after injury was observed, relative to WT mice. The results from these studies demonstrate an in vivo mechanistic relationship between FVIIa, Egr-1 and the inflammatory response in keratinocyte function during the wound healing process.

AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes

“…A proper inflammatory response is required for skin wound repair. Too little inflammation could lead to tissue unhealed28. On the other hand, prolonged inflammation leads to pathological healing such as scarring29.…”

Transition from inflammation to proliferation: a critical step during wound healing

“…Early growth response 1 (EGR1) is a zinc finger transcription factor essential for skin wound healing in adults. Its deletion leads to impaired migration of keratinocytes and inflammatory cells, reduced myofibroblast differentiation and thus delayed healing [ 166 , 167 ]. In contrast, overexpression of EGR1 in wounds of adult mice and rats increased re-epithelialisation, angiogenesis, collagen deposition and wound contraction by up-regulating several growth factors [ 168 ].…”

Gene expression analysis of an epidermolysis bullosa simplex Dowling‐Meara cell line by subtractive hybridization: recapitulation of cellular differentiation, migration and wound healing

“…In synergy with coagulation factor 7 (F7), F3 is primarily known to participate in the initiation of thrombus formation in the extrinsic coagulation cascade (49,50), an important step in wound healing. F3 is also expressed in skin keratinocytes and was found by Xu et al (51) to be crucial for positively influencing keratinocyte migration, re-epithelialization, leucocyte migration and inflammatory signalling in keratinocytes during wound healing. This characteristic also matches the observation of Morley et al (33) who showed in a scratch wound assay that re-epithelialization occurred significantly faster in EBS cells than in the control cell lines, which again fits our model of an activated 'wound healing state' of EBS-DM keratinocytes.…”